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Robust in vivo differentiation of t(8;21)-positive acute myeloid leukemia blasts to neutrophilic granulocytes induced by treatment with dasatinib

Leukemia volume 24, pages 1779–1781 (2010)Cite this article

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The groundbreaking discovery of all-trans retinoic acid as a potent inducer of in vivo differentiation in acute promyelocytic leukemia has provided the first proof of concept of clinically active differentiation therapy in cancer.1 The vast majority of acute myeloid leukemia (AML) patients, however, are nonresponsive to single-agent all-trans retinoic acid or to other agents inducing differentiation in vitro.

We present the case of a 52-year-old male patient diagnosed in March 2006 with de novo AML, a white blood count (WBC) of 32 000/μl, 65% bone marrow (BM) blasts (highly expressing CD117/c-Kit), a 45,X,-Y, t(8;21)(q22;q22) karyotype, wild-type flt-3 and an activating c-Kit mutation (exon 17 N822K). According to the sequencing chromatogram (generated as previously described2), the c-Kit mutation was only present in a sub-population of cells (data not shown). The patient relapsed three times after standard treatments, including allogeneic blood stem cell transplantation from a human leukocyte antigen-identical sibling in April 2007 and salvage treatment with topotecan and cytosine arabinoside in August 2007. Being faced with this highly chemo-resistant AML, we offered the patient palliative treatment with the multi-kinase inhibitor dasatinib (a known inhibitor of c-Kit3) to control leukemic regrowth. After the patient gave informed consent, dasatinib was started on 13 September 2007, at a dose of 70 mg b.i.d. and 7 days later at 100 mg b.i.d., on the basis of the knowledge that in Core Binding Factor (CBF) leukemias, c-Kit is usually overexpressed and/or activated by point mutations;4 either mechanism is considered to function as a ‘second hit’ oncogenic lesion complementing the leukemic fusion proteins RUNX1/RUNX1T1 (AML1/ETO) or CBFβ/MYH11.5 At that time, the subclone with the c-Kit exon 17 N822K mutation was no longer detectable by direct sequencing (not shown), indicating clonal evolution.

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Acknowledgements

We thank Roland Weis for support of flow cytometry studies, Tobias Berg for providing photomicrographs, Marcus M Schittenhelm (Tübingen) for helpful experimental advice, and Clara Nervi, Phillip Koeffler and Richard Schlenk for helpful discussions. This work was supported by Dr Mildred Scheel-Program Deutsche Krebshilfe (HB ref. No. 108660), German Research Foundation (DFG) research fellowship (NC) and CCI (BMBF) Tandem Project (JH).

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Author notes

  1. N Chevalier and H Becker: Research Fellowship Program at the Department of Hematology and Oncology.

  2. N Chevalier and M L Solari: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, University of Freiburg, Medical Center, Freiburg, Germany

    N Chevalier, M L Solari, H Becker, M Pantic, F Gärtner, R Wäsch & M Lübbert

  2. Centre of Chronic Immunodeficiency Breisacherstr,

    A Maul-Pavicic

  3. University of Freiburg, Medical Center,, Freiburg, Germany

    A Maul-Pavicic

  4. Department of Infectious Diseases and Travel Medicine, University of Freiburg, Medical Center, Freiburg, Germany

    J Hübner

  5. Department of General Pathology, Institute of Pathology, University of Freiburg, Freiburg, Germany

    A Schmitt-Gräff

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  1. N Chevalier
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Chevalier, N., Solari, M., Becker, H. et al. Robust in vivo differentiation of t(8;21)-positive acute myeloid leukemia blasts to neutrophilic granulocytes induced by treatment with dasatinib. Leukemia 24, 1779–1781 (2010). https://doi.org/10.1038/leu.2010.151

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